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== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
The intrinsically disordered protein p15(PAF) regulates DNA replication and repair by binding to the proliferating cell nuclear antigen (PCNA) sliding clamp. We present the structure of the human p15(PAF)-PCNA complex. Crystallography and NMR show the central PCNA-interacting protein motif (PIP-box) of p15(PAF) tightly bound to the front-face of PCNA. In contrast to other PCNA-interacting proteins, p15(PAF) also contacts the inside of, and passes through, the PCNA ring. The disordered p15(PAF) termini emerge at opposite faces of the ring, but remain protected from 20S proteasomal degradation. Both free and PCNA-bound p15(PAF) binds DNA mainly through its histone-like N-terminal tail, while PCNA does not, and a model of the ternary complex with DNA inside the PCNA ring is consistent with electron micrographs. We propose that p15(PAF) acts as a flexible drag that regulates PCNA sliding along the DNA and facilitates the switch from replicative to translesion synthesis polymerase binding.
Cellular genomes are highly vulnerable to perturbations to chromosomal DNA replication. Proliferating cell nuclear antigen (PCNA), the processivity factor for DNA replication, plays a central role as a platform for recruitment of genome surveillance and DNA repair factors to replication forks, allowing cells to mitigate the threats to genome stability posed by replication stress. We identify the E3 ubiquitin ligase TRAIP as a new factor at active and stressed replication forks that directly interacts with PCNA via a conserved PCNA-interacting peptide (PIP) box motif. We show that TRAIP promotes ATR-dependent checkpoint signaling in human cells by facilitating the generation of RPA-bound single-stranded DNA regions upon replication stress in a manner that critically requires its E3 ligase activity and is potentiated by the PIP box. Consequently, loss of TRAIP function leads to enhanced chromosomal instability and decreased cell survival after replication stress. These findings establish TRAIP as a PCNA-binding ubiquitin ligase with an important role in protecting genome integrity after obstacles to DNA replication.


Structure of p15(PAF)-PCNA complex and implications for clamp sliding during DNA replication and repair.,De Biasio A, de Opakua AI, Mortuza GB, Molina R, Cordeiro TN, Castillo F, Villate M, Merino N, Delgado S, Gil-Carton D, Luque I, Diercks T, Bernado P, Montoya G, Blanco FJ Nat Commun. 2015 Mar 12;6:6439. doi: 10.1038/ncomms7439. PMID:25762514<ref>PMID:25762514</ref>
TRAIP is a PCNA-binding ubiquitin ligase that protects genome stability after replication stress.,Hoffmann S, Smedegaard S, Nakamura K, Mortuza GB, Raschle M, Ibanez de Opakua A, Oka Y, Feng Y, Blanco FJ, Mann M, Montoya G, Groth A, Bekker-Jensen S, Mailand N J Cell Biol. 2016 Jan 4;212(1):63-75. doi: 10.1083/jcb.201506071. Epub 2015 Dec, 28. PMID:26711499<ref>PMID:26711499</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

Revision as of 15:14, 13 January 2016

Crystal Structure of Human PCNA in complex with a TRAIP peptideCrystal Structure of Human PCNA in complex with a TRAIP peptide

Structural highlights

4ztd is a 6 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum

Function

[PCNA_HUMAN] Auxiliary protein of DNA polymerase delta and is involved in the control of eukaryotic DNA replication by increasing the polymerase's processibility during elongation of the leading strand. Induces a robust stimulatory effect on the 3'-5' exonuclease and 3'-phosphodiesterase, but not apurinic-apyrimidinic (AP) endonuclease, APEX2 activities. Has to be loaded onto DNA in order to be able to stimulate APEX2. Plays a key role in DNA damage response (DDR) by being conveniently positioned at the replication fork to coordinate DNA replication with DNA repair and DNA damage tolerance pathways. Acts as a loading platform to recruit DDR proteins that allow completion of DNA replication after DNA damage and promote postreplication repair: Monoubiquitinated PCNA leads to recruitment of translesion (TLS) polymerases, while 'Lys-63'-linked polyubiquitination of PCNA is involved in error-free pathway and employs recombination mechanisms to synthesize across the lesion.[1] [2]

Publication Abstract from PubMed

Cellular genomes are highly vulnerable to perturbations to chromosomal DNA replication. Proliferating cell nuclear antigen (PCNA), the processivity factor for DNA replication, plays a central role as a platform for recruitment of genome surveillance and DNA repair factors to replication forks, allowing cells to mitigate the threats to genome stability posed by replication stress. We identify the E3 ubiquitin ligase TRAIP as a new factor at active and stressed replication forks that directly interacts with PCNA via a conserved PCNA-interacting peptide (PIP) box motif. We show that TRAIP promotes ATR-dependent checkpoint signaling in human cells by facilitating the generation of RPA-bound single-stranded DNA regions upon replication stress in a manner that critically requires its E3 ligase activity and is potentiated by the PIP box. Consequently, loss of TRAIP function leads to enhanced chromosomal instability and decreased cell survival after replication stress. These findings establish TRAIP as a PCNA-binding ubiquitin ligase with an important role in protecting genome integrity after obstacles to DNA replication.

TRAIP is a PCNA-binding ubiquitin ligase that protects genome stability after replication stress.,Hoffmann S, Smedegaard S, Nakamura K, Mortuza GB, Raschle M, Ibanez de Opakua A, Oka Y, Feng Y, Blanco FJ, Mann M, Montoya G, Groth A, Bekker-Jensen S, Mailand N J Cell Biol. 2016 Jan 4;212(1):63-75. doi: 10.1083/jcb.201506071. Epub 2015 Dec, 28. PMID:26711499[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Burkovics P, Hajdu I, Szukacsov V, Unk I, Haracska L. Role of PCNA-dependent stimulation of 3'-phosphodiesterase and 3'-5' exonuclease activities of human Ape2 in repair of oxidative DNA damage. Nucleic Acids Res. 2009 Jul;37(13):4247-55. doi: 10.1093/nar/gkp357. Epub 2009, May 13. PMID:19443450 doi:10.1093/nar/gkp357
  2. ↑ Motegi A, Liaw HJ, Lee KY, Roest HP, Maas A, Wu X, Moinova H, Markowitz SD, Ding H, Hoeijmakers JH, Myung K. Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks. Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12411-6. Epub 2008 Aug 21. PMID:18719106 doi:0805685105
  3. ↑ Hoffmann S, Smedegaard S, Nakamura K, Mortuza GB, Raschle M, Ibanez de Opakua A, Oka Y, Feng Y, Blanco FJ, Mann M, Montoya G, Groth A, Bekker-Jensen S, Mailand N. TRAIP is a PCNA-binding ubiquitin ligase that protects genome stability after replication stress. J Cell Biol. 2016 Jan 4;212(1):63-75. doi: 10.1083/jcb.201506071. Epub 2015 Dec, 28. PMID:26711499 doi:http://dx.doi.org/10.1083/jcb.201506071

4ztd, resolution 2.20Å

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